The importance of CXCR4 expression in tumor stroma as a potential biomarker in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer mortality in the world. A characteristic feature of this cancer is that a large part of the tumor volume is composed of a stroma with different cells and factors. Among these, we can highlight the cytokines, which perform their function through binding to their receptors. Given the impact of the CXCR4 receptor in the interactions between tumor cells and their microenvironment and its involvement in important signaling pathways in cancer, it is proposed as a very promising prognostic biomarker and as a goal for new targeted therapies. Numerous studies analyze the expression of CXCR4 but we suggest focusing on the expression of CXCR4 in the stroma. METHODS: Expression of CXCR4 in specimens from 33 patients with PDAC was evaluated by immunohistochemistry techniques and matched with clinicopathological parameters, overall and disease-free survival rates. RESULTS: The percentage of stroma was lower in non-tumor tissue (32.4 ± 5.2) than in tumor pancreatic tissue (67.4 ± 4.8), P-value = 0.001. The level of CXCR4 expression in stromal cells was diminished in non-tumor tissue (8.7 ± 4.6) and higher in tumor pancreatic tissue (23.5 ± 6.1), P-value = 0.022. No significant differences were identified in total cell count and inflammatory cells between non-tumor tissue and pancreatic tumor tissue. No association was observed between CXCR4 expression and any of the clinical or pathological data, overall and disease-free survival rates. Analyzing exclusively the stroma of tumor samples, the CXCR4 expression was associated with tumor differentiation, P-value = 0.05. CONCLUSIONS: In this study, we reflect the importance of CXCR4 expression in the stroma of patients diagnosed with PDAC. Our results revealed a high CXCR4 expression in the tumor stroma, which is related to a poor tumor differentiation. On the contrary, we could not find an association between CXCR4 expression and survival and the rest of the clinicopathological variables. Focusing the study on the CXCR4 expression in the tumor stroma could generate more robust results. Therefore, we consider it key to develop more studies to enlighten the role of this receptor in PDAC and its implication as a possible biomarker.

Glioblastoma Proximity to the Lateral Ventricle Alters Neurogenic Cell Populations of the Subventricular Zone.

Despite current strategies combining surgery, radiation, and chemotherapy, glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Tumor location plays a key role in the prognosis of patients, with GBM tumors located in close proximity to the lateral ventricles (LVs) resulting in worse survival expectancy and higher incidence of distal recurrence. Though the reason for worse prognosis in these patients remains unknown, it may be due to proximity to the subventricular zone (SVZ) neurogenic niche contained within the lateral wall of the LVs. We present a novel rodent model to analyze the bidirectional signaling between GBM tumors and cells contained within the SVZ. Patient-derived GBM cells expressing GFP and luciferase were engrafted at locations proximal, intermediate, and distal to the LVs in immunosuppressed mice. Mice were either sacrificed after 4 weeks for immunohistochemical analysis of the tumor and SVZ or maintained for survival analysis. Analysis of the GFP+ tumor bulk revealed that GBM tumors proximal to the LV show increased levels of proliferation and tumor growth than LV-distal counterparts and is accompanied by decreased median survival. Conversely, numbers of innate proliferative cells, neural stem cells (NSCs), migratory cells and progenitors contained within the SVZ are decreased as a result of GBM proximity to the LV. These results indicate that our rodent model is able to accurately recapitulate several of the clinical aspects of LV-associated GBM, including increased tumor growth and decreased median survival. Additionally, we have found the neurogenic and cell division process of the SVZ in these adult mice is negatively influenced according to the presence and proximity of the tumor mass. This model will be invaluable for further investigation into the bidirectional signaling between GBM and the neurogenic cell populations of the SVZ.

Predictive factors of satisfaction and quality of life after immediate breast reconstruction using the BREAST-Q©.

AIMS AND OBJECTIVES: To analyse quality of life and satisfaction after immediate breast reconstruction due to cancer and its determining factors. BACKGROUND: Studying breast reconstruction is important because of its frequency and variability. In addition to the surgical results, it is necessary to analyse the quality of life and patient satisfaction using a specific tool. DESIGN METHODS: An ambispective design was used (n = 101; α = 0.05; precision = 10%), studying anthropometric, sociocultural data, Fagerström test and the BREAST-Q© questionnaire. A logistic regression analysis was performed to identify variables associated with quality of life and satisfaction. RESULTS: Mean age of the patients on diagnosis was 44.87 ± 8.5 years. Forty-one of the patients were carried out a skin-sparing mastectomy (42.7%). Immediate reconstruction was performed with implant in 73 (74.5%). The domains on the BREAST-Q© for quality of life with the lowest scores were physical well-being chest (74) and sexual well-being (61.5). The satisfaction domain with the lowest score was with the breast (59). The variables associated with the worst quality of life in the physical well-being chest domain were the skin-sparing mastectomy (OR, 4.2; 95% confidence interval (CI), 1.2-14.1) and lymphedema (OR, 12.9; 95% CI, 1.0-159.9). Antibody treatment was associated with a worse score on the psychosocial well-being domain (OR, 4.25; 95% CI, 1.0-18.0) and sexual well-being domain (OR, 7.34; 95% CI, 0.9-54.6). Satisfaction was associated with nicotine dependence on the breast and outcome scale. The higher the dependence on nicotine, the greater the dissatisfaction with the breasts (OR, 2.41; 95% CI, 1.1-5.3) and with the result (OR, 2.45; 95% CI, 1.0-5.9). CONCLUSIONS: The type of treatment and lymphedema modify the patients' quality of life. Nicotine dependence is associated with lower satisfaction with the breast and with the outcome. RELEVANCE TO CLINICAL PRACTICE: This study suggests the need for multidisciplinary attention during the first year of adjuvant treatment despite the benefits of immediate reconstruction. It shows the need for preoperative assessment of the level of nicotine dependence, anxiety and depression of smoking patients before preoperative counselling.

Quality of life and anxiety in women with breast cancer before and after treatment.

OBJECTIVES: to determine the quality of life and anxiety in patients with breast cancer and the changes they experience after treatments. METHOD: prospective study. Breast cancer statistics (n=339, confidence=95%, accuracy= ± 5.32%). The quality of life questionnaires (QLQ) used were QLQ C-30 and QLQ Br23, and the State-Trait Anxiety Inventory (STAI) was used for anxiety. A multivariate analysis was performed to identify variables associated with baseline quality of life and anxiety as well as pre- and post-treatment differences. Authorization was obtained from the Ethics Committee, and informed consent was provided by all patients. RESULTS: the baseline quality of life dimensions with the lowest score were future prospects (46.0/100) and sexual enjoyment (55.7/100). The dimensions with the highest score were body image (94.2/100) and role (93.3/100). The most disturbing symptoms were insomnia, fatigue and concern about hair loss. After treatment, the dimensions of physical function, role, body image, financial concerns and symptomatology worsened, whereas emotional function and future prospects improved. Severe anxiety presented as a state (48.6%) and as a trait (18.2%). The highest baseline state anxiety was associated with married-widowed status and anxiolytic medication. The greatest trait anxiety was associated with an inactive work situation, anxiolytic medication, breast swelling and advanced stage at diagnosis. After treatment, anxiety significantly decreased. CONCLUSIONS: After treatment, the quality of life score was positively modified, while state and trait anxiety decreased.

Quality of life and anxiety in women with breast cancer before and after treatment / Qualidade de vida e ansiedade em mulheres com câncer de mama antes e depois do tratamento / Calidad de vida, ansiedad antes y después del tratamiento en mujeres con cáncer de mama

ABSTRACT Objectives: to determine the quality of life and anxiety in patients with breast cancer and the changes they experience after treatments. Method: prospective study. Breast cancer statistics (n=339, confidence=95%, accuracy= ± 5.32%). The quality of life questionnaires (QLQ) used were QLQ C-30 and QLQ Br23, and the State-Trait Anxiety Inventory (STAI) was used for anxiety. A multivariate analysis was performed to identify variables associated with baseline quality of life and anxiety as well as pre- and post-treatment differences. Authorization was obtained from the Ethics Committee, and informed consent was provided by all patients. Results: the baseline quality of life dimensions with the lowest score were future prospects (46.0/100) and sexual enjoyment (55.7/100). The dimensions with the highest score were body image (94.2/100) and role (93.3/100). The most disturbing symptoms were insomnia, fatigue and concern about hair loss. After treatment, the dimensions of physical function, role, body image, financial concerns and symptomatology worsened, whereas emotional function and future prospects improved. Severe anxiety presented as a state (48.6%) and as a trait (18.2%). The highest baseline state anxiety was associated with married-widowed status and anxiolytic medication. The greatest trait anxiety was associated with an inactive work situation, anxiolytic medication, breast swelling and advanced stage at diagnosis. After treatment, anxiety significantly decreased. Conclusions: After treatment, the quality of life score was positively modified, while state and trait anxiety decreased.

RESUMO Objetivos: determinar a qualidade de vida e a ansiedade de pacientes com câncer de mama e as mudanças sofridas após os tratamentos. Método: estudo prospectivo. Incidentes de câncer de mama (n = 339, nível de confiança = 95%, precisão = ± 5,32%). Os questionários de qualidade de vida foram o QLQC-30 e o QLQBr23 e o de ansiedade, o Inventário de Ansiedade Traço Estado (IDATE; em inglês: State-Trait Anxiety Inventory - STAI). Foi feita uma análise multivariada para identificar as variáveis associadas à qualidade de vida e à ansiedade iniciais e as diferenças entre os períodos pré e pós tratamento. Foi obtido consentimento informado e uma autorização do Comitê de Ética. Resultados: as dimensões iniciais da qualidade de vida com as menores pontuações foram: perspectivas futuras (46,0/100) e prazer sexual (55,7/100). Dimensões com as pontuações mais altas: imagem corporal (94,2/100) e funcional (93,3/100). Os sintomas mais perturbadores foram: insônia, fadiga e preocupação com a queda de cabelo. Após os tratamentos, pioraram: função física, funcional, imagem corporal, preocupações financeiras e sintomatologia. A função emocional e as perspectivas futuras melhoraram. A ansiedade grave foi apresentada como estado (48,6%) e como traço (18,2%). A maior ansiedade inicial como estado estava associada ao estado civil de casada ou viúva e ao uso de medicamentos ansiolíticos. A maior ansiedade como traço estava associada a: situação inativa no trabalho, medicamentos ansiolíticos, inchaço nas mamas e estágios avançados no momento do diagnóstico. Após os tratamentos, a ansiedade diminui significativamente. Conclusões: após os tratamentos, a pontuação da qualidade de vida é modificada positivamente e a ansiedade como estado e traço diminui.

RESUMEN Objetivos: determinar calidad de vida y ansiedad en pacientes con cáncer de mama y cambios experimentados tras tratamientos. Método: estudio prospectivo. Casos incidentes de cáncer de mama(n=339;seguridad=95%;precisión=±5,32%). Los cuestionarios de calidad de vida fueron: QLQC-30, QLQBr23, y ansiedad: STAI. Se realizó análisis multivariado para identificar variables asociadas a calidad de vida y ansiedad basales y las diferencias pre y post tratamiento. Se obtuvo autorización del comité de ética y consentimiento informado. Resultados: las dimensiones de calidad de vida basales con menor puntuación son: perspectivas de futuro(46,0/100), disfrute sexual(55,7/100). Dimensiones con mayor puntuación: imagen corporal(94,2/100), funcionalidad del rol(93,3/100). Los síntomas más perturbadores fueron: insomnio, fatiga, preocupación por pérdida del cabello. Tras tratamientos, empeoraron: función física, del rol, imagen corporal, dificultades financieras y sintomatología. Mejoraron la función emocional y perspectivas de futuro. Presentaron ansiedad severa como estado 48,6% y como rasgo 18,2%. La mayor ansiedad estado basal se asoció con estado civil casadas-viudas y medicación ansiolítica. La mayor ansiedad rasgo con: situación laboral inactiva, medicación ansiolítica, hinchazón mamaria y estadios avanzados al diagnóstico. Tras los tratamientos, disminuye significativamente la ansiedad. Conclusiones: tras los tratamientos, la puntuación de calidad de vida se modifica positivamente y la ansiedad como estado y como rasgo disminuye.

Repercusión de los criterios ACOSOG Z0011 sobre la indicación de la linfadenectomía axilar y el control locorregional en mujeres con ganglio centinela metastásico. Resultados preliminares tras cuatro años de aplicación clínica / Repercussion of the ACOSOG-Z0011 criteria for the indication of axillary lymph node dissection and locoregional control in women with metastatic sentinel lymph node. Preliminary results after four years of clinical application

Objetivo. Evaluar los cambios en la indicación de la linfadenectomía axilar (LA), su eficacia para eliminar enfermedad residual y control locorregional, tras la adopción de los criterios del estudio ACOSOG Z0011. Pacientes y método. Estudio observacional retrospectivo en mujeres con carcinoma infiltrante de mama tratadas quirúrgicamente, entre febrero 2010 y mayo de 2014. Todas las pacientes fueron valoradas según los criterios del ensayo clínico ACOSOG Z0011 para el manejo del ganglio centinela (GC) metastatizado. Resultados. Un total de 118 enfermas presentaron afectación del GC, y de ellas 53 (44,92% de las pacientes con GC metastásico) evitaron la LA por la aplicación de los criterios ACOSOG Z0011. La mayoría de estas mujeres (73,58%) presentaron afectación micrometastásica del GC. El grupo de enfermas con mayor beneficio fueron las pacientes con conservación mamaria, ya que el 58,23% de estas enfermas evitaron la LA. Se realizaron un total de 65 LA por afectación metastásica del GC sin que se evidenciase metástasis en la grasa axilar en 37 (55,2%) pacientes. Conclusiones. La adopción de los criterios ACOSOG Z0011 permite disminuir la indicación de la LA, especialmente en aquellas mujeres sometidas a un procedimiento conservador. A pesar de la introducción de estos criterios, existe un grupo significativo de mujeres (55%) en quienes la LA no demuestra afectación ganglionar de la grasa axilar y no obtienen ningún beneficio con la misma (AU)

Objective. To evaluate changes in the indication of axillary lymph node dissection (ALND), its effectiveness in eliminating residual disease, and locoregional control after the adoption of the ACOSOG Z0011 study criteria. Patients and methods. Retrospective study in women with invasive breast cancer treated surgically from February 2010 to May 2014. All women were evaluated according to the ACOSOG-Z0011 trial criteria for the management of metastasized sentinel lymph node (SLN). Results. A total of 118 women had SLN involvement. Application of the ACOSOG Z0011 criteria avoided ALND in 53 of the 118 patients (44.92% of the patients with metastatic SLN), most of them (73.58%) with micrometastases. The benefit was greater in women undergoing conservative surgery, because 58.23% of these women avoided ALND. A total of 65 ALND were performed for metastatic SLN, of which 37 (55.2%) showed no involvement of axillary fat. Conclusions. Adoption of the ACOSOG Z0011 criteria decreases the indication of ALND, especially in women undergoing conservative surgery. Despite the introduction of these criteria, there is a significant percentage of women (55%) in whom ALND shows no lymph node involvement in axillary fat and produces no benefit (AU)

Carcinoma adenoide quístico parotídeo: soluciones estéticas y funcionales / Adenoid cystic carcinoma of the parotid: an aesthetic and functional solutions

El carcinoma adenoide quístico supone el 10-30% de las neoplasias malignas parotídeas, su tratamiento se basa en una parotidectomía que incluya el tumor con un adecuado margen de seguridad y la radioterapia postoperatoria dado que permite mejorar el control locorregional de la enfermedad. Revisamos un caso que permite exponer el manejo de las secuelas funcionales y estéticas derivadas de su tratamiento. Consideramos adecuada la reconstrucción inmediata del nervio facial cuando se encuentra clínicamente afecto o englobado por el tumor; así como suplir el defecto de volumen posparotidectomía con un colgajo local. Proponemos la anastomosis nerviosa con injerto de nervio sural de las ramas del nervio facial afectas y el relleno del defecto volumen posparotidectomía con un colgajo de fascia temporo-parietal (AU)

Adenoid cystic carcinoma represents 10-30% of all malignant neoplasms in the parotid gland. Treatment is a formal parotidectomy, which includes removing the tumour with an adequate margin and postoperative radiotherapy to improve the locoregional control of the disease. We report a case in order to present the management of the functional and aesthetic consequences obtained from its treatment. When the facial nerve is clinical affected or involved by the tumour, it requires resection and an immediate reconstruction. We suggest the sural nerve graft for the reconstruction of the affected facial branches and the temporo-parietal fascia flap to fill the volume left by the parotidectomy (AU)

Recurrent adenocarcinoma of the sinonasal tract.

BACKGROUND: Adenocarcinomas arising from the nasal cavity and paranasal sinus are malignant tumours that are not of minor salivary gland origin, and they do not demonstrate histopathological features of sinonasal intestinal-type adenocarcinoma. These adenocarcinomas are divided into low- and high-grade subtypes. We herein present a case to highlight the significance of a correct histological diagnosis for treatment and follow-up. CASE REPORT: We report a case of a recurrent low-grade adenocarcinoma arising in the left nasal cavity and extending to the ethmoid, maxillary sinus and orbital floor. No facial deformity or proptosis was present. The diagnosis was made by analysis of a sample taken by biopsy and CT-MRI. We performed a radical maxillectomy and reconstruction with a temporalis muscle flap and a titanium mesh for the orbital floor. DISCUSSION: Low-grade adenocarcinomas of the sinonasal tract are a challenge for the pathologist to differentiate from benign adenomas and high-grade adenocarcinomas, but the distinction is important because the treatment and prognosis differ. Treatment success is determined by complete surgical excision. We also suggest the usefulness of PET to detect recurrence during follow-up.

Quinoxaline 1,4-di-N-oxide and the potential for treating tuberculosis.

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed.

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents.

We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.

Benzo[b]thiophene-6-carboxamide 1,1-dioxides: inhibitors of human cancer cell growth at nanomolar concentrations.

Benzo[b]thiophenesulfonamide 1,1-dioxide derivatives (BTS) were described as candidate antineoplastic drugs. In the hope of finding new compounds with improved antitumour activity and reduced toxicity, we have designed and synthesized a small series of benzo[b]thiophene-6-carboxamide 1,1-dioxide derivatives (BTC) structurally related with the best reported BTS. Growth inhibition of HTB-54, CCRF-CEM and HeLa tumour cells lines at nanomolar concentrations was exhibited by some of the BTC. Hydrophobic substituents on the carboxamide group increased cytotoxicity but substitution by a hydroxy group diminished it, thus pointing to the electronic density on benzo[b]thiophene nucleus as a determinant factor. The process of cell death induced by BTC derivatives was further analyzed in CCRF-CEM cells, where these compounds induced apoptosis in a time and dose-dependent manner and cell cycle arrest at S phase. BTC derivatives also induced a significant increase in intracellular ROS levels in this cell line. Previous treatment of the cells with the antioxidant N-acetyl-cysteine abrogated the induction of apoptosis by BTC indicating that ROS generation is a previous event required to trigger the BTC induced apoptotic process.

DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide.

The heterocyclic N-oxide, 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1), shows promising antitumor activity in preclinical studies, but there is a continuing need to explore new compounds in this general structural category. In the work described here, we examined the properties of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide (9h). We find that 9h causes redox-activated, hypoxia-selective DNA cleavage that mirrors the lead compound, tirapazamine, in both mechanism and potency. Furthermore, we find that 9h displays hypoxia-selective cytotoxicity against human cancer cell lines.

New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents.

Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents, obtaining biological values similar to the reference compound, Rifampin (RIF).

Heterocyclic-2-carboxylic acid (3-cyano-1,4-di-N-oxidequinoxalin-2-yl)amide derivatives as hits for the development of neglected disease drugs.

Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC(50) values in the same order as the anti-chagasic drug, nifurtimox.

Selective activity against Mycobacteriumtuberculosis of new quinoxaline 1,4-di-N-oxides.

New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 microg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4'-fluoro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 microg/mL and SI > 500).

Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1, 4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives

A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis.

This study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H(37)Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 (a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis.

In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide.

OBJECTIVES: To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB). METHODS: Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824. RESULTS: Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of

Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives.

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC(50) less than 1 microM against the 3D7 strain. Derivative 1 demonstrated high potency (IC(50)= 0.63 microM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.

Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives.

The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia.